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TNF-α/IL-1β-licensed hADSCs alleviate cholestatic liver injury and fibrosis in mice via COX-2/PGE2 pathway

BACKGROUND: Adipose tissue-derived stem cell (ADSC) transplantation has been shown to be effective for the management of severe liver disorders. Preactivation of ADSCs enhanced their therapeutic efficacy. However, these effects have not yet been examined in relation to cholestatic liver injury. METH...

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Autores principales: Luan, Xiaoyu, Chen, Peng, Li, Yaxin, Yuan, Xinying, Miao, Longyu, Zhang, Pengyu, Cao, Qilong, Song, Xiaomin, Di, Guohu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127380/
https://www.ncbi.nlm.nih.gov/pubmed/37095581
http://dx.doi.org/10.1186/s13287-023-03342-3
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author Luan, Xiaoyu
Chen, Peng
Li, Yaxin
Yuan, Xinying
Miao, Longyu
Zhang, Pengyu
Cao, Qilong
Song, Xiaomin
Di, Guohu
author_facet Luan, Xiaoyu
Chen, Peng
Li, Yaxin
Yuan, Xinying
Miao, Longyu
Zhang, Pengyu
Cao, Qilong
Song, Xiaomin
Di, Guohu
author_sort Luan, Xiaoyu
collection PubMed
description BACKGROUND: Adipose tissue-derived stem cell (ADSC) transplantation has been shown to be effective for the management of severe liver disorders. Preactivation of ADSCs enhanced their therapeutic efficacy. However, these effects have not yet been examined in relation to cholestatic liver injury. METHODS: In the present study, a cholestatic liver injury model was established by bile duct ligation (BDL) in male C57BL/6 mice. Human ADSCs (hADSCs) with or without tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) pretreatment were administrated into the mice via tail vein injections. The efficacy of hADSCs on BDL-induced liver injury was assessed by histological staining, real-time quantitative PCR (RT-qPCR), Western blot, and enzyme-linked immune sorbent assay (ELISA). In vitro, the effects of hADSC conditioned medium on the activation of hepatic stellate cells (HSCs) were investigated. Small interfering RNA (siRNA) was used to knock down cyclooxygenase-2 (COX-2) in hADSCs. RESULTS: TNF-α/IL-1β preconditioning could downregulate immunogenic gene expression and enhance the engraftment efficiency of hADSCs. Compared to control hADSCs (C-hADSCs), TNF-α/IL-1β-pretreated hADSCs (P-hADSCs) significantly alleviated BDL-induced liver injury, as demonstrated by reduced hepatic cell death, attenuated infiltration of Ly6G + neutrophils, and decreased expression of pro-inflammatory cytokines TNF-α, IL-1β, C-X-C motif chemokine ligand 1 (CXCL1), and C-X-C motif chemokine ligand 2 (CXCL2). Moreover, P-hADSCs significantly delayed the development of BDL-induced liver fibrosis. In vitro, conditioned medium from P-hADSCs significantly inhibited HSC activation compared to that from C-hADSCs. Mechanistically, TNF-α/IL-1β upregulated COX-2 expression and increased prostaglandin E2 (PGE2) secretion. The blockage of COX-2 by siRNA transfection reversed the benefits of P-hADSCs for PGE2 production, HSC activation, and liver fibrosis progression. CONCLUSION: In conclusion, our results suggest that TNF-α/IL-1β pretreatment enhances the efficacy of hADSCs in mice with cholestatic liver injury, partially through the COX-2/PGE2 pathway. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-023-03342-3.
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spelling pubmed-101273802023-04-26 TNF-α/IL-1β-licensed hADSCs alleviate cholestatic liver injury and fibrosis in mice via COX-2/PGE2 pathway Luan, Xiaoyu Chen, Peng Li, Yaxin Yuan, Xinying Miao, Longyu Zhang, Pengyu Cao, Qilong Song, Xiaomin Di, Guohu Stem Cell Res Ther Research BACKGROUND: Adipose tissue-derived stem cell (ADSC) transplantation has been shown to be effective for the management of severe liver disorders. Preactivation of ADSCs enhanced their therapeutic efficacy. However, these effects have not yet been examined in relation to cholestatic liver injury. METHODS: In the present study, a cholestatic liver injury model was established by bile duct ligation (BDL) in male C57BL/6 mice. Human ADSCs (hADSCs) with or without tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) pretreatment were administrated into the mice via tail vein injections. The efficacy of hADSCs on BDL-induced liver injury was assessed by histological staining, real-time quantitative PCR (RT-qPCR), Western blot, and enzyme-linked immune sorbent assay (ELISA). In vitro, the effects of hADSC conditioned medium on the activation of hepatic stellate cells (HSCs) were investigated. Small interfering RNA (siRNA) was used to knock down cyclooxygenase-2 (COX-2) in hADSCs. RESULTS: TNF-α/IL-1β preconditioning could downregulate immunogenic gene expression and enhance the engraftment efficiency of hADSCs. Compared to control hADSCs (C-hADSCs), TNF-α/IL-1β-pretreated hADSCs (P-hADSCs) significantly alleviated BDL-induced liver injury, as demonstrated by reduced hepatic cell death, attenuated infiltration of Ly6G + neutrophils, and decreased expression of pro-inflammatory cytokines TNF-α, IL-1β, C-X-C motif chemokine ligand 1 (CXCL1), and C-X-C motif chemokine ligand 2 (CXCL2). Moreover, P-hADSCs significantly delayed the development of BDL-induced liver fibrosis. In vitro, conditioned medium from P-hADSCs significantly inhibited HSC activation compared to that from C-hADSCs. Mechanistically, TNF-α/IL-1β upregulated COX-2 expression and increased prostaglandin E2 (PGE2) secretion. The blockage of COX-2 by siRNA transfection reversed the benefits of P-hADSCs for PGE2 production, HSC activation, and liver fibrosis progression. CONCLUSION: In conclusion, our results suggest that TNF-α/IL-1β pretreatment enhances the efficacy of hADSCs in mice with cholestatic liver injury, partially through the COX-2/PGE2 pathway. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-023-03342-3. BioMed Central 2023-04-24 /pmc/articles/PMC10127380/ /pubmed/37095581 http://dx.doi.org/10.1186/s13287-023-03342-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Luan, Xiaoyu
Chen, Peng
Li, Yaxin
Yuan, Xinying
Miao, Longyu
Zhang, Pengyu
Cao, Qilong
Song, Xiaomin
Di, Guohu
TNF-α/IL-1β-licensed hADSCs alleviate cholestatic liver injury and fibrosis in mice via COX-2/PGE2 pathway
title TNF-α/IL-1β-licensed hADSCs alleviate cholestatic liver injury and fibrosis in mice via COX-2/PGE2 pathway
title_full TNF-α/IL-1β-licensed hADSCs alleviate cholestatic liver injury and fibrosis in mice via COX-2/PGE2 pathway
title_fullStr TNF-α/IL-1β-licensed hADSCs alleviate cholestatic liver injury and fibrosis in mice via COX-2/PGE2 pathway
title_full_unstemmed TNF-α/IL-1β-licensed hADSCs alleviate cholestatic liver injury and fibrosis in mice via COX-2/PGE2 pathway
title_short TNF-α/IL-1β-licensed hADSCs alleviate cholestatic liver injury and fibrosis in mice via COX-2/PGE2 pathway
title_sort tnf-α/il-1β-licensed hadscs alleviate cholestatic liver injury and fibrosis in mice via cox-2/pge2 pathway
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127380/
https://www.ncbi.nlm.nih.gov/pubmed/37095581
http://dx.doi.org/10.1186/s13287-023-03342-3
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